Generally speaking, it has turned out that a medicament orally administered is absorbed in the small intestine and hardly reaches the lower part of the small intestine and the large intestine (colon and rectum). Up until now, there was known a pharmaceutical composition which was soluble in the intestine, to transmit a medicament to the lower part of the small intestine and to the large intestine. In this composition, the coating thereof is dissolved according to the rise in pH thereby releasing the medicament in the composition. However, the pH in the digestive organs of a living body changes during the day, is influenced by food, and further is different between individuals. Accordingly, it has been found that such medicaments are unexpectedly absorbed in the upper part of the small intestine or the composition is excreted without disintegration.
Another idea for transmitting a medicament to the large intestine, utilizing a medicament which has been chemically modified, i.e. a prodrug, has been designed. However, it also has the defect that it is absorbed in the upper part of the small intestine. Further, the medicament is caused to be administered in large amounts in order to transmit it to the large intestine at a sufficiently high concentration with the attendant increase in side effects. Furthermore, in a prodrug, a modified group is metabolized and released, and thus it is considered that side effects accompanying the toxicity to occur. For example, salicylazosulfapyridine, which is a prodrug of 5-aminosalicyclic acid, is reported by Peppercorn M. A. et al (see J. Pharmacol. Exp. Ther. 181: 555-562, 1972). It is reported that the modified group, sulfapyridine, has toxicity (International Pharmacy Journal, 1(6), 223-226, 1987).
On the other hand, it has been found that peptides, such as insulin, vasopressin, etc., administered orally, are degraded and inactivated by digestive enzymes, such as peptidase, in the small intestine, etc. and its bioavailability is extremely low. Therefore, it is a reasonable consideration that the absorption from the large intestine in which digestive enzymes hardly exist, may be effective. However, no pharmaceutical composition for oral administration for such purpose has been developed until now.
Metabolism in the large intestine is almost exclusively conducted by intestinal bacteria, different from other digestive mechanisms. In order to obtain high molecular compounds for coating which can be degraded specifically in the large intestine, this structure should be effectively constituted by considering the action of the intestinal bacteria. For example, cellulose, which is known to be metabolized by Eschericia coli, has an essential factor for high molecular compounds degraded in the large intestine, and has been utilized in various ways. However, cellulose and its derivatives are difficult to control the rate of degradation.
Another chemical bond severed by the action of intestinal bacteria is an aromatic-azo bond. It is known that the bond is reduced to an amino group by azo-reducing enzyme released by intestinal bacteria, as follows: ##STR5##
A coating polymer for delivering a medicament to the lower part of the digestive tract, by using the said enzymatic reaction, is proposed in the U.S. Pat. No. 4,663,308. It is a polymer derived from ethylenically unsaturated monomers (e.g. vinyl acetate, acrylic acid, methacrylic acid etc.) as the main chain, cross-linked by a divinylazobenzene of the formula: ##STR6## wherein R.sup.a and R.sup.b are each, independently, hydrogen, halogen, nitro or other substituents.
However, the cross-linked polymer is unstable to light and is difficult to be prepared at high conversion of the monomer to a polymer. Therefore, it has such defects that its solubility in various solvents is low and that its film-forming property is not good. Furthermore, it is difficult to precisely design the molecular structure so as to control the rate of release, and the like.